Most neural prosthetic devices, such as cochlear implants, retinal implants, and cardiac pacemakers, work on the principle of electrical stimulation. (Wilson, B. S., Finley, C. C., Lawson, D. T., Wolford, R. D., Eddington, D. K., and Rabinowitz, W. M. (1991). Better speech recognition with cochlear implants. Nature, 352(6332):236-238; Hornig, R., Laube, T., Walter, P., Velikay-Parel, M., Bornfeld, N., Feucht, M., Akguel, H., Rssler, G., Alteheld, N., Notarp, D. L., Wyatt, J., and Richard, G. (2005). A method and technical equipment for an acute human trial to evaluate retinal implant technology. Journal of Neural Engineering, 2(1):S129; Epstein, A. E., DiMarco, J. P., Ellenbogen, K. A., Estes, N. M., Freedman, R. A., Gettes, L. S., Gillinov, A. M., Gregoratos, G., Hammill, S. C., Hayes, D. L., et al. (2008). Acc/aha/hrs 2008 guidelines for device-based therapy of cardiac rhythm abnormalities a report of the American college of cardiology/American heart association task force on practice guidelines (writing committee to revise the acc/aha/naspe 2002 guideline update for implantation of cardiac pacemakers and antiarrhythmia devices) developed in collaboration with the American association for thoracic surgery and society of thoracic surgeons. Journal of the American College of Cardiology, 51(21):e1-e62). Typically, these devices electrically stimulate biological cells such as peripheral and cranial nerves, vestibular hair cells, cochlear nerves, and cardiac cells.
With regard to cochlear implants, a set of electrodes are placed into the cochlea. Different electrodes stimulate different auditory nerve fibers (ANFs) via current pulses based on sound frequencies with high frequencies towards the base of the cochlea and low frequencies towards the apex of the cochlea, thus mimicking the tonotopic organization of the cochlea. Because of electrical current spread, it is difficult to stimulate discrete ANFs according to respective frequencies. Specifically, the processing of speech in background noise and musical sounds to the desired perception of cochlear implant users still remains a significant problem to be addressed because, normally, speech and music has a large number of frequencies at various volume/intensity levels. (O'Leary, S. J., Richardson, R. R., and McDermott, H. J. (2009). Principles of design and biological approaches for improving the selectivity of cochlear implant electrodes. Journal of Neural Engineering, 6(5):055002; Firszt, J. B., Koch, D. B., Downing, M., and Litvak, L. (2007). Current steering creates additional pitch percepts in adult cochlear implant recipients. Otology & Neurotology, 28(5):629-636; Limb, C. J. and Roy, A. T. (2014). Technological, biological, and acoustical constraints to music perception in cochlear implant users. Hearing Research, 308(0):13-26. Music: A window into the hearing brain).
Peripheral neuropathy is a condition related to the damage and/or malfunctioning of a nerve or a group of nerves of the peripheral nervous system. Electromyography is one of the most common techniques used to detect or diagnose peripheral neuropathy. Like cochlear implants, electromyography also works on the principle of electrical stimulation of muscles/nerves. As electrical stimulation is not specific, it will not stimulate a single nerve but large groups of peripheral nerve bundles. Interestingly, there are recent reports that infrared lasers can invoke in vivo responses. Wells et al. (2005) reported 2 to 10 μm wavelength infrared lasers invoked responses from rat sciatic nerve. (Wells, J., Kao, C., Jansen, E. D., Konrad, P., and Mahadevan-Jansen, A. (2005). Application of infrared light for in vivo neural stimulation. Journal of Biomedical Optics, 10(6):064003-064003-12). The likely mechanism of infrared stimulation is a temperature rise due to photothermal interaction and membrane capacitance changes. (Wells, J., Kao, C., Konrad, P., Milner, T., Kim, J., Mahadevan-Jansen, A., and Jansen, E. D. (2007). Biophysical mechanisms of transient optical stimulation of peripheral nerve. Biophysical Journal, 93(7):2567-2580; Shapiro, M. G., Homma, K., Villarreal, S., Richter, C.-P., and Bezanilla, F. (2012). Infrared light excites cells by changing their electrical capacitance. Nature Communications, 3:736).
Infrared lasers can also be used to stimulate auditory nerve fibers (ANFs) of deaf animals, giving better spatial resolution as compared to electrical stimulation. (Izzo, A. D., Richter, C.-P., Jansen, E. D., and Walsh, J. T. (2006). Laser stimulation of the auditory nerve. Lasers in Surgery and Medicine, 38(8):745-753; Izzo, A. D., Walsh, J. T., Jansen, E. D., Bendett, M., Webb, J., Ralph, H., and Richter, C.-P. (2007b). Optical parameter variability in laser nerve stimulation: a study of pulse duration, repetition rate, and wavelength. Biomedical Engineering, IEEE Transactions on, 54(6): 1108-1114; Littlefield, P. D., Vujanovic, I., Mundi, J., Matic, A. I., and Richter, C.-P. (2010). Laser stimulation of single auditory nerve fibers. The Laryngoscope, 120(10):2071-2082; Rajguru, S. M., Matic, A. I., Robinson, A. M., Fishman, A. J., Moreno, L. E., Bradley, A., Vujanovic, I., Breen, J., Wells, J. D., Bendett, M., et al. (2010). Optical cochlear implants: evaluation of surgical approach and laser parameters in cats. Hearing Research, 269(1): 102-111).
Shapiro et al. (2012) showed that the absorption of infrared laser energy causes a local temperature rise which does not affect a particular membrane channel directly, but rather changes cell membrane capacitance. However, along with the neurons, the infrared laser increases the temperature of the surrounding tissue as well, which can cause thermal damage or unwanted stimulation.
The inventors sought to develop an alternative technology to electrical stimulation with a special focus on stimulation of neurons, cardiomyocytes, auditory nerve fibers, and for applications to diagnosing and treating peripheral neuropathy. The inventors show herein that plasmonic heating can be used to stimulate electrically excitable biological cells with localized heating and without the bulk heating that is present when infrared light is used.
Nanoparticles are a fundamental building block of nanotechnology and find applications in various fields like electronics, chemistry, catalysis, pharmaceuticals, biology, etc. (Shipway, A. N., Katz, E., and Willner, I. (2000). Nanoparticle arrays on surfaces for electronic, optical, and sensor applications. Chem Phys Chem, 1(1):18-52; Daniel, M.-C. and Astruc, D. (2004). Gold nanoparticles: assembly, supramolecular chemistry, quantum-size-related properties, and applications toward biology, catalysis, and nanotechnology. Chemical Reviews, 104(1):293-346; Otsuka, H., Nagasaki, Y., and Kataoka, K. (2003). Pegylated nanoparticles for biological and pharmaceutical applications. Advanced Drug Delivery Reviews, 55(3):403-419; Salata, O. V. (2004). Applications of nanoparticles in biology and medicine. Journal of Nanobiotechnology, 2(1):3).
Nanoparticles are defined as particles having a diameter less than 100 nm. (Kruis, F. E., Fissan, H., and Peled, A. (1998). Synthesis of nanoparticles in the gas phase for electronic, optical and magnetic applications a review. Journal of Aerosol Science, 29(5):511-535). Their physical and chemical properties change dramatically with particle size. Metallic nanoparticles, such as gold (Au) nanoparticles, have strong surface interactions with electromagnetic fields because of the relative availability of free electrons in conduction bands. In surface plasmon resonance (SPR), light, which is an electromagnetic wave, interacts with metal nanoparticles causing conduction band electrons to oscillate. The oscillation becomes maximum at a particular wavelength of light. (FIG. 1) The SPR peak can be tuned with particle properties, such as size and shape. For gold nanoparticles, the SPR peak is at about 520 nm. Gold nanoparticles absorb and scatter light very efficiently. For example, for small size particles (<20 nm in diameter), absorption dominates. As size increases, scattering efficiency increases because higher-order electron oscillations start to play a significant role. As gold nanoparticles are not good emitters of light, absorbed light generates heat. (Coronado, E. A., Encina, E. R., and Stefani, F. D. (2011). Optical properties of metallic nanoparticles: manipulating light, heat and forces at the nanoscale. Nanoscale, 3:4042-4059; Huang, X. and El-Sayed, M. A. (2010). Gold nanoparticles: optical properties and implementations in cancer diagnosis and photothermal therapy. Journal of Advanced Research, 1(1): 13-28). This localized heating due to SPR is also known as plasmonic heating. Thus, for local heating applications small size Au particles (20 nm and smaller) are used, while for scattering applications like imaging, larger particles are utilized (30 nm and larger).
Given the difficulties in the current state of the art at the time of the invention, the inventors examined if localized SPR can be used to stimulate electrically excitable biological cells such as neurons or cardiomyocytes utilizing visible light as the energy source. The inventors investigated stimulation of cardiomyocytes (from neonatal rats) and SH-SY5Y mammalian neurons using gold nanoparticles and visible light.